The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12619001147178
Ethics application status
Approved
Date submitted
29/07/2019
Date registered
16/08/2019
Date last updated
26/08/2019
Date data sharing statement initially provided
16/08/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Cancer Molecular Screening and Therapeutics (MoST) Program Substudy Addendum 6 substudy 14-15: Larotrectinib
Scientific title
Single arm, open label, signal seeking, phase IIa trial of the activity of Larotrectinib in patients with advanced NTRK1-3 positive tumours.
Secondary ID [1] 297752 0
CTC0141-Addendum 6
Universal Trial Number (UTN)
U1111-1182-6652
Trial acronym
MoST Addendum 6
Linked study record
This record is an addendum to the MoST framework (ACTRN12616000908437). The MoST framework protocol consists of 1/molecular screening (genomic analysis to determine whether participants are suitable for a sub-study) and 2/ sub-study design structure (study treatment for specific genomic expression/participant population). Additionally, the sub-study shares the same study objectives and outcomes as the framework. Hence, this is a substudy that linked to ACTRN12616000908437.

Health condition
Health condition(s) or problem(s) studied:
Cancer 312089 0
Condition category
Condition code
Cancer 310648 310648 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Larotrectinib will be taken orally by the participant at home, at a dose of 100 mg twice daily. The Larotrectinib dosage may be reduced to 75 mg or 50 mg twice daily if participant experiences intolerance toxicity. Larotrectinib is to be taken continuously until disease progression is documented or when the participant experiences intolerable toxicity or withdraws for another reason. Participants will be asked to return unused drug and empty drug containers at each return visit. The Pharmacy Department at participating institutions will maintain a record of drugs dispensed for each participant.
Intervention code [1] 313991 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 319495 0
The primary end point is disease control defined as: 1. Objective tumour response, based on complete and partial responses using cancer specific response criteria or 2. Time to progressive (TTP) disease exceeds the documented time to progressive disease on the last treatment prior to substudy entry by at least 1.3 times (TTP2/TTP1 > 1.3). Or exceeds 6 months if TTP1 is not evaluable. Where disease evaluation is not based on CT scans alternative validated guidelines, such as Gynecologic Cancer Intergroup (GCIG) and Prostate Cancer Working Group 2 (PCWG2) criteria will be employed. Where radiological progression cannot be assessed, evidence for clinical progression will be documented. These data will be collected from participant questionnaires, such as quality of life per the QLQ-C30 version 3 or The Brief Pain Inventory, or clinical reports to supplement the primary outcome.
Timepoint [1] 319495 0
CT or MRI scans for disease evaluation will take place every 8 weeks until disease progression.
Secondary outcome [1] 368427 0
Overall survival (OS) (death from any cause).
Timepoint [1] 368427 0
For the duration of the study.
Secondary outcome [2] 368429 0
Safety and tolerability of treatment (rates of adverse events).
All adverse events (AEs), including event grading as per NCI CTCAE criteria, will be captured from the first dose of study treatment until 30 days after cessation of study treatment. Reported AEs (eg. diarrhoea, gastrointestinal disorder) by participants will be documented by study site staff and subsequently transcript onto study electronic data capturing (EDC) system. In order to evaluate the safety and tolerability of the study treatment, the entered AE types, frequency and severity in the EDC will be analysed.
Timepoint [2] 368429 0
Adverse events will be recorded from the first dose of study treatment until 30 days after cessation of study treatment.
Secondary outcome [3] 368430 0
Health related quality of life during treatment will be assessed using the EORTC QLQ-C30 and The Brief Pain Inventory Forms
Timepoint [3] 368430 0
Every 4 weeks during treatment and every 8 weeks during follow-up until disease progression

Eligibility
Key inclusion criteria
Inclusion Criteria – molecular screening
1. Male or female patients, aged 18 years and older, with pathologically confirmed advanced and/or metastatic solid cancer of any histologic type or an earlier diagnosis of a poor prognosis cancer;
2. Sufficient and accessible tissue for molecular screening;
3. Patients receiving their last line of standard treatment or who have received and failed all standard anticancer therapy (where standard therapy exists) or have documented unsuitability for any further standard anticancer therapy. Poor prognosis cancers or cancers with low expected response rate to standard treatment (in the opinion of the investigator and based on available evidence) may be screened on an earlier line of treatment.
a. Failure is defined as either progression of disease (clinical or radiological) or intolerance to standard therapy resulting in the discontinuation of the therapy.
b. Documented unsuitability for further standard therapy includes known hypersensitivity, organ dysfunction or other patient factors that would make therapy unsuitable in the judgement of the responsible investigator;
4. ECOG performance status equal or less than 2;
5. Willing and potentially able to comply with study requirements, including treatment, timing and/or nature of required assessments;

It is the intention to screen patients who are in principle wishing to take part in a MoST substudy if they are found to have an appropriate tumour biomarker and are still eligible for enrolment at the time of the treatment phase (substudy).

To be eligible for treatment in a substudy, patients must continue to meet all of the inclusion criteria and none of the exclusion criteria specified for entry into molecular screening at the time of registration to a treatment substudy. In addition, they must meet all the inclusion criteria and none of the exclusion criteria in the substudy addendum at the time of registration.

Inclusion Criteria – substudy
1. Confirmation of molecular eligibility by the molecular tumour board;
2. Received and failed all standard anticancer therapy or have documented unsuitability for any further standard therapy, if standard therapy exists;
3. Clinical or radiological progression on or following last anticancer therapy;
4. Adequate organ system function as assessed by the following minimal laboratory requirements (within 7 days prior to first administration of study drug):
a. bone marrow function; platelets equal or more than 100 x 109/L, ANC equal or more than 1.5 x 109/L and haemoglobin equal or more than 9g/dL (5.6mmol/L);
b. liver function; ALT/AST equal or less than 3x ULN (in the absence of liver metastases, equal or less than 5 x ULN for patients with liver involvement) and total bilirubin equal or less than 1.5xULN;
c. renal function; serum creatinine equal or less than 1.5xULN
5. Patients with tumours harbouring somatic NTRK1-3 rearrangements/ fusions
6. For non primary CNS cancers, at least one site of measurable disease according to RECIST version 1.1, if evaluable disease is present
7. For primary CNS tumours, the following additional inclusion criteria must be met:
a. Radiation as first line therapy, if given, completed > 12 weeks prior to C1D1 of study treatment
b. At least one site of bi-dimensionally measurable disease (confirmed by magnetic resonance imaging [MRI] and evaluable by RANO criteria), with the size of at least one of the measurable lesions equal or more than 1 cm in each dimension and noted on more than one imaging slice
c. Baseline imaging done while on a stable dose of steroid medication for at least 5 days immediately before the MRI.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusions criteria - molecular screening
1. Suitable for standard therapy or accepted standard care, if the patient has not been previously treated;
2. Specific comorbidities or conditions (e.g. psychiatric) or concomitant medications which may contraindicate participation and/or interact with the investigational product;
3. Other co-morbidities or conditions that may compromise assessment of key outcomes or in the opinion of the clinician, limit the ability of the patient to comply with the protocol;
4. For non central nervous system (CNS) cancers, patients with symptomatic CNS involvement of his/her cancer are excluded. Subjects with stable neurological function on stable doses of steroids/anti-epileptics over 4 weeks, and with no evidence of CNS progression within 12 weeks prior to screening are eligible;
5. History of another malignancy within 2 years prior to molecular screening registration are excluded unless adequately treated and determined free of progressive and metastatic disease for at least 6 months. Patients with a past history of adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or superficial transitional cell carcinoma of the bladder can be included;
6. Pregnancy, lactation or inadequate contraception.

Exclusion criteria - substudy
1. Contraindications to investigational product, as listed in the substudy addendum and outlined in the Investigator Brochure appended to each substudy module;
2. Known history of hypersensitivity to active or inactive components of investigational product;
3. Previous treatment with the same agent or same class of agent;
4. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment:
- Radiation therapy, surgery or tumour embolization within 14 days prior to the first dose of study treatment. Palliative radiotherapy (for analgesia) is acceptable only if the irradiated field does not include target lesions;
- Immunotherapy within 28 days prior to the first dose of study treatment;
- Chemotherapy, biologic therapy or hormonal therapy within 14 days or 5 half-lives of a drug, prior to the first dose of study treatment, or until recovery from previous therapy (whichever is longer);
5. Administration of any investigational treatment within 30 days or 5 half-lives (whichever is longer) prior to receiving the first dose of study treatment;
6. Any additional exclusion criteria specified in the relevant substudy addendum.
7. Patients unable or unwilling to swallow capsules
8. Prior treatment with a NTRK inhibitor
9. Treatment with strong inhibitors or inducers of CYP3A4 within 7 days of registration
10. Patients who require treatment with an enzyme-inducing anti-epileptic drug

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
As described in the framework protocol (ACTRN12616000908437), substudies with greater than or equal to 3 out of 16 responding patients, will in general be sufficiently interesting to investigate further. As a general rule, substudies with less than 3 out of 16 responses will be considered to not support the molecular hypothesis behind the substudy.

If some activity is recognised in a 16 patient substudy cohort but further information is needed to inform development of phase II testing, iterative substudies may be opened to enrich for patients that harbour a specific common biomarker or histologic cancer subtype. Each such iteration would constitute a new substudy for the purposes of this framework.

The sample size and guiding definitions of what constitutes an interesting signal are determined empirically as the investigators considered these numbers of patients as sufficient for signal-seeking purpose.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 13440 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [2] 13441 0
St George Hospital - Kogarah
Recruitment hospital [3] 13442 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [4] 13443 0
The Canberra Hospital - Garran
Recruitment hospital [5] 13444 0
Linear Clinical Research - Nedlands
Recruitment hospital [6] 13445 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [7] 13446 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [8] 13447 0
Royal Hobart Hospital - Hobart
Recruitment hospital [9] 13448 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [10] 13449 0
Princess Alexandra Hospital - Woolloongabba
Recruitment postcode(s) [1] 26045 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 26046 0
2217 - Kogarah
Recruitment postcode(s) [3] 26047 0
2050 - Camperdown
Recruitment postcode(s) [4] 26048 0
2605 - Garran
Recruitment postcode(s) [5] 26049 0
6009 - Nedlands
Recruitment postcode(s) [6] 26050 0
3000 - Melbourne
Recruitment postcode(s) [7] 26051 0
5000 - Adelaide
Recruitment postcode(s) [8] 26052 0
7000 - Hobart
Recruitment postcode(s) [9] 26053 0
0810 - Tiwi
Recruitment postcode(s) [10] 26054 0
4102 - Woolloongabba

Funding & Sponsors
Funding source category [1] 302276 0
Government body
Name [1] 302276 0
Office for Health and Medical Research
Address [1] 302276 0
Locked Bag 961 North Sydney NSW 2059
Country [1] 302276 0
Australia
Funding source category [2] 303410 0
Other Collaborative groups
Name [2] 303410 0
Australian Genomic Cancer Medicine Centre (AGCMC)
Address [2] 303410 0
Kinghorn Cancer Centre,
370 Victoria Street,
Darlinghurst NSW 2010
Country [2] 303410 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country
Australia
Secondary sponsor category [1] 302150 0
None
Name [1] 302150 0
Address [1] 302150 0
Country [1] 302150 0
Other collaborator category [1] 280883 0
Other Collaborative groups
Name [1] 280883 0
Australian Genomic Cancer Medicine Centre
Address [1] 280883 0
Kinghorn Cancer Centre,
370 Victoria Street,
Darlinghurst NSW 2010
Country [1] 280883 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302952 0
St Vincent's Hospital Ethics Committee
Ethics committee address [1] 302952 0
Translational Research Centre,
97-105 Boundary Street,
Darlinghurst NSW 2010
Ethics committee country [1] 302952 0
Australia
Date submitted for ethics approval [1] 302952 0
29/06/2019
Approval date [1] 302952 0
21/08/2019
Ethics approval number [1] 302952 0

Summary
Brief summary
This is a substudy of the Cancer Molecular Screening and Therapeutics (MoST) Program, which is registered on ANZCTR with ID ACTRN12616000908437. This substudy will evaluate the activity of Larotrectinib in patients with advanced tumours harbouring NTRK1-3 rearrangements

Who is it for?
You may be eligible to join the study if you are aged 18 years and older, with pathologically confirmed advanced and/or metastatic solid cancer of any cell type or an earlier diagnosis of a poor prognosis cancer and your tumour harbouring somatic NTRK1-3 rearrangements. You will also have to receive all standard anticancer therapy.

Study details:
Participants will continue to consume 100mg of Larotrectinib, twice daily, for as long as they and their doctor agree there is a benefit from treatment. Participants will undergo imaging assessments at 8 weekly intervals or as clinically indicated in order to evaluate tumour response. Safety and tolerability of treatment and health related quality of life during treatment will be assessed at 4 weekly intervals.

We cannot guarantee that participants will receive any benefits from this study. This study is being carried out to improve the way we treat cancer patients who may have limited treatment options available to them. It is hoped that Larotrectinib will be well tolerated and will improve outcomes for future patients, however, there may be no clear benefit from participation in this study.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 91958 0
Dr Subotheni Thavaneswaran
Address 91958 0
Garvan Institute of Medical Research,
The Kinghorn Cancer Centre,
370 Victoria Street,
Darlinghurst NSW 2010
Country 91958 0
Australia
Phone 91958 0
+61 2 9355 5655
Fax 91958 0
+61 (0)2 9355 5872
Email 91958 0
s.thavaneswaran@garvan.org.au
Contact person for public queries
Name 91959 0
Dr Lucille Sebastian
Address 91959 0
NHMRC Clinical Trials Centre,
Medical Foundation Building
Levels 4-6,
92-94 Parramatta Road,
Camperdown NSW 2050
Country 91959 0
Australia
Phone 91959 0
+61 2 9562 5000
Fax 91959 0
Email 91959 0
most@ctc.usyd.edu.au
Contact person for scientific queries
Name 91960 0
Dr Subotheni Thavaneswaran
Address 91960 0
Garvan Institute of Medical Research,
The Kinghorn Cancer Centre,
370 Victoria Street,
Darlinghurst NSW 2010
Country 91960 0
Australia
Phone 91960 0
+61 2 9355 5655
Fax 91960 0
+61 (0)2 9355 5872
Email 91960 0
s.thavaneswaran@garvan.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
There are no plans for this to occur at this time and participant consent is required for data sharing.
What supporting documents are/will be available?
No other documents available
Summary results
No Results